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A universal feature of clinical dry eye is hyperosmolarity of the tears resulting from their accelerated evaporation due to dysfunction of tear- and oil-producing ocular glands. A key adaptive response to dryness\/hyperosmolarity is release of tear-stabilizing mucin by conjunctival goblet cells. Yet the mechanisms mediating this response to hyperosmolarity remain poorly understood. In this study of freshly excised rat conjunctiva, perforated-patch recordings revealed that during sustained hyperosmolarity, the development of a nonspecific cation (NSC) conductance depolarizes the goblet cells to a near-optimal voltage for the tonic activation of their voltage-gated calcium channels (VGCCs). In turn, as demonstrated by high-resolution membrane capacitance measurements, VGCC activation boosts the exocytotic response of conjunctival goblet cells to neural input. However, over time, VGCC activation also increases the vulnerability of these cells to the lethality of hyperosmolarity. Viability assays further revealed that hyperosmotic-induced goblet cell death is critically dependent on P2X<jats:sub>7<\/jats:sub> receptor channels. Similar to the yin-yang impact of VGCCs on goblet cell physiology and pathobiology, P2X<jats:sub>7<\/jats:sub> activation not only compromises goblet cell viability but also enhances exocytotic activity. Thus, the NSC\/VGCC and P2X<jats:sub>7<\/jats:sub> purinoceptor pathways are components of a previously unappreciated high-gain\/high-risk adaptive strategy to combat ocular dryness. These pathways boost release of tear-stabilizing mucin at the risk of jeopardizing the viability of the conjunctival goblet cells, whose loss is a histopathological hallmark of irreversible mucin-deficient dry eye. <\/jats:p>","DOI":"10.1152\/ajpcell.00086.2020","type":"journal-article","created":{"date-parts":[[2020,4,29]],"date-time":"2020-04-29T20:47:14Z","timestamp":1588193234000},"page":"C1305-C1315","source":"Crossref","is-referenced-by-count":13,"title":["How goblet cells respond to dry eye: adaptive and pathological roles of voltage-gated calcium channels and P2X<sub>7<\/sub> purinoceptors"],"prefix":"10.1152","volume":"318","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3221-3011","authenticated-orcid":false,"given":"Donald G.","family":"Puro","sequence":"first","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, Michigan"},{"name":"Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, 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